Angiotensin II (AngII) plays an essential role in the pathogenesis of human hypertension. Increasing evidence suggests that AngII induces hypertension primarily by triggering the intrarenal renin-angiotensin system (RAS), particularly the renin response in the collecting duct (CD) that results in generation of endogenous AngII. Along this line, (pro)renin receptor (PRR), a newly discovered component of tissue RAS and activator of renin and prorenin, is colocalized with renin in the CD and its expression is similarl stimulated by AngII. Preliminary studies demonstrated that AngII-induced hypertension along with the elevated PRR and renin expression was all blunted by COX-2 inhibition or EP4 antagonism. On the other hand, overexpression of PRR in IMCD cells is shown to increase COX-2 expression. Based on these observations, we hypothesize that COX-2/EP4 and PRR/renin positively regulate each other's expression/activity in the CD forming a vicious cycle which amplifies the local renin response for maximal AngII generation and then ENaC activation during AngII-induced hypertension. Three specific aims have been designed to test the general hypothesis. Aim 1 uses CD-specific EP4 knockout model to test the hypothesis that the activation of CD EP4 receptor results in sequential activation of PRR, renin, and ENaC, ultimately leading to elevation of BP in response to AngII infusion. Aim 2 uses mice with CD-specific overexpression or deletion of renin to test the hypothesis that the activity of local RAS n the distal nephron positively affects renal prostaglandin synthesis. The alteration of renal COX-2 transcriptional activity is monitored by in vivo imaging of luciferase knock-in reporter mice following AngII infusion. Aim 3 employs a novel PRR decoy peptide coupled with the intramedullary infusion technique to test the hypothesis that inhibition of renal medullary PRR attenuates local renin response and BP during AngII infusion. New information resulted from this proposal is expected to offer new insight into the renal mechanism of AngII-induced hypertension and also help define the therapeutic potential of the newly developed PRR decoy peptide for treatment of hypertension and kidney disease.